Networks of small caliber blood vessels, termed vasa vasorum, are confined to the outer media and adventitia layers of major large caliber blood vessels; however, these vessels proliferate and invade the intima during atherosclerosis and other conditions of vasculitis. Increasing data suggests that the permeability, inflammatory cell recruitment and bleeding properties of plaque neovascularization promote atherosclerosis and its complications. The neovascular network invading atherosclerotic lesions may also serve as a more efficient portal for drug penetration into diseased arteries to control their occlusion and plaque instability. In diabetes, we have recently shown the tendency for plaques to acquire neovascularization is significantly increased and accelerates atherosclerosis. Thus, the characterization of molecules displayed on plaque neovascularization in diabetes can identify important ligand/receptor interactions that take place on this unique microvascular endothelium and mediate pathologic functions. These molecular targets can be exploited to deliver molecular imaging agents or drugs to the pathologic neovascularization and minimize their effects on normal arteries. We hypothesize angiogenic plaque capillaries display unique molecules that promote atherosclerosis in diabetes, which will useful to understand and modify its functions and to deliver more selective treatments. Our preliminary studies have identified a receptor that is highly expressed on plaque neovascularization, but not on the endothelium or normal arteries. We will use receptor-specific targeting peptides that have been optimized by our collaborators to validate ligand-directed nanoparticle delivery to diabetic plaque neovascularization in vivo. We will also use a novel animal model of diabetes-induced plaque angiogenesis and phage display methods to screen and identify a repertoire of vascular- accessible, high affinity ligand/receptor partners on plaque neovascularization in diabetes. Results from this exploratory study will enhance our molecular understanding of plaque vasa vasorum and its role in progression of atherosclerosis and vascular complications. Our screen should identify other plaque neovascularization binding candidates and will refine methods for in vivo validation of plaque angiogenesis-dependent targeting that will drive future development of targeting agents for diagnostics and treatments to reduce macrovascular complications in patients with or without diabetes.